Use Of Aminoglycosides Research Articles

NpmC, a novel A1408 16S rRNA methyltransferase in the gut of humans and animals

16S rRNA methyltransferases that act on residue A1408, NpmA and NpmB, confer high-level resistance to virtually all the aminoglycosides, but their reports are scarce. Analysing metagenomic projects in a One Health context, we identified in human and animal gut microbiomes from China and Canada a novel gene, npmC, that shares an identity of 91.5% with npmA, and up to 92.7% at amino acidic level. The protein encoded by this gene presents the conserved motifs required for A1408 methylation. Expression of the gene resulted in high-level of resistance to 4,5-disubstituted 2-deoxystreptamine (2-DOS) and to 4-monosubstituted 2-DOS aminoglycosides, as well as a moderate resistance to 4,6-disusbstituted 2-DOS aminoglycosides, including the last resort aminoglycoside plazomicin. Methylation at residue A1408 was further confirmed by mass spectrometry assays. The analysis of the npmC gene background revealed that its genetic context is associated to different insertion sequences that could mobilise it. Similarities in the genetic context between npmC and npmA suggest that they share a common ancestor. The immediate genetic context of this methyltransferase suggests high relationship to the Eubacteriales order. This finding enlarges the list of the true pan-aminoglycoside 16S rRNA methyltransferases, that threaten the usefulness and development of next-generation aminoglycosides.

Ribosomal A site binding pattern differs between Arm methyltransferases from clinical pathogens and a natural producer of aminoglycosides

The extensive use of aminoglycosides to treat bacterial infections has led to significant resistance, posing a global health threat. Recent clinical reports highlight high levels of aminoglycoside resistance due to Arm/Kam methyltransferases, which methylate specific nucleotides in 16S rRNA, preventing antibiotic binding to the ribosome. This study compared the ribosomal A site binding patterns of Arm methyltransferases from clinical pathogens (ArmA, RmtB, RmtC, and RmtD) with those of the Sgm methyltransferase from a natural aminoglycoside producer. We introduced single mutations near the G1405 nucleotide in helix 44 of 16S rRNA to assess their impact on the methylation ability of Arm methyltransferases in E. coli cells with homogeneous mutant ribosomes. We evaluated how these mutations affected bacterial viability in cells with mixed and homogeneous ribosome populations and determined the minimal inhibitory concentration of kanamycin to assess their impact on Arm enzyme activity. Notably, Sgm methyltransferase exhibited a distinct methylation pattern compared to Arm methyltransferases from clinical strains. Structural comparisons of Sgm, RmtB, and RmtC revealed different spatial orientations of key amino acids involved in ribosomal binding, highlighting evolutionary differences. This research enhances understanding of Arm methyltransferases and lays the groundwork for designing inhibitors to combat this potent form of antibiotic resistance.

Sensorineural Hearing Loss in Patients With the m.1555A>G Mutation in the MTRNR1 Gene.

Mutations in the MTRNR1 gene of mitochondrial DNA are associated with non-syndromic hearing loss and increased susceptibility to aminoglycoside ototoxicity. The aim of our study was to determine the clinical characteristics of sensorineural hearing loss caused by the m.1555A>G mutation in MTRNR1. An observational retrospective study of the m.1555A>G mutation was conducted in patients with suspected hereditary bilateral sensorineural hearing loss in the Department of Otolaryngology of the Marqués de Valdecilla University Hospital (Cantabria, Spain) and in 100 controls with normal hearing. The m.1555A>G mutation was found in 82 individuals from 20 different families and in none of the controls. Variable degrees of hearing loss were observed, ranging from normal hearing to profound deafness. Patients with a history of streptomycin administration exhibited significantly more pronounced hearing loss. The onset of hearing loss occurred from childhood to adulthood, with progression or stability over the years. No associated vestibular alterations or other clinical manifestations outside the ear were found. Two cochlear implant recipients showed significant improvement in speech comprehension. Patients with the m.1555A>G mutation in the MTRNR1 gene often develop bilateral, symmetric sensorineural hearing loss, predominantly affecting high frequencies, worsened by streptomycin administration. This mutation does not affect the vestibular function. The variability in the severity of hearing loss, the heterogeneity of phenotypic expression, and the presence of carrier individuals with normal hearing may indicate the existence of modifying factors, both environmental and genetic. Cochlear implantees showed a good response in terms of speech intelligibility. Genetic testing for this mutation is recommended in patients with a family history of hearing loss to prevent the use of aminoglycosides if the mutation is found. 4 Laryngoscope, 2024.

Prevalence and mechanisms of aminoglycoside resistance among drug-resistant Pseudomonas aeruginosa clinical isolates in Iran

BackgroundAminoglycosides have been a cornerstone of the treatment of nosocomial infections caused by Pseudomonas aeruginosa for over 80 years. However, escalating emergence of resistance poses a significant challenge. Therefore, this study aimed to investigate the prevailing patterns of aminoglycoside resistance among clinical isolates of P. aeruginosa in Iran; as well as the underlying resistance mechanisms observed in patients referred to Ardabil hospitals.MethodsA total of 200 isolates from five hospitals were evaluated. The resistance profiles of P. aeruginosa isolates to tobramycin, amikacin, and netilmicin were determined using the disk diffusion method. The capacity of aminoglycoside-resistant isolates to form biofilms was assessed through a phenotypic assay, and the results were confirmed using the gene amplification technique. The presence of genes associated with aminoglycoside resistance was detected using polymerase chain reaction (PCR). Quantitative reverse transcription PCR (qRT-PCR) was performed to measure the expression levels of genes encoding the MexXY-OprM efflux pump and PhoPQ two-component system (TCS).ResultsThe prevalence of aminoglycoside-resistant P. aeruginosa isolates was 48%, with 94.7% demonstrating multidrug resistance (MDR). All aminoglycoside-resistant P. aeruginosa strains exhibited biofilm-forming capabilities and harbored all the genes associated with biofilm production. Among the nine genes encoding 16S rRNA methylase and aminoglycoside-modifying enzymes, three genes were detected in these isolates: aac(6’)-Ib (85.4%), ant(2’’)-Ia (18.7%), and aph(3’)-VI (3.1%). Additionally, all aminoglycoside-resistant P. aeruginosa isolates carried mexY and phoP genes, although the expression levels of mexY and phoP were 75% and 87.5%, respectively.ConclusionGiven the considerably high prevalence of aminoglycoside-resistant P. aeruginosa strains, urgent measures are warranted to transition towards the use of novel aminoglycosides and to uphold vigilant surveillance of resistance patterns.

Aminoglycoside utilization in elderly inpatients: Implications for renal health and adverse outcomes

BackgroundAminoglycosides, maintaining antimicrobial efficacy, are considered for combating multidrug-resistant pathogens. Their contemporary use, combined with vigilant preventive strategies, may not universally lead to lasting renal complications in elderly inpatients. MethodsThis study examined data from the National Health Insurance Registry Database, focusing on elderly inpatients (aged 60 and above) hospitalized between 2000 and 2017 due to pneumonia, urinary tract infections, or bacteremia. Patients treated with aminoglycosides were compared to those receiving other antibiotics. Patient follow-up continued until the occurrence of renal disease, death, or for three months post-discharge, based on diagnoses coded in the International Classification of Diseases. ResultsAmong 938,052 elderly inpatients admitted for infections, 29.19 % were prescribed aminoglycosides. Patients receiving aminoglycosides tended to be younger and had fewer associated health conditions compared to those treated with other antibiotics. The overall incidence of renal disease was 2.03 % during hospitalization and it increased to 17.45 % at the three-month follow-up. While no increased risk for renal disease was observed in the aminoglycoside group compared to other antibiotics, it correlated with higher rates of death and intensive care unit transfer. Specific comorbidities, such as diabetes mellitus, heart failure, and liver disease, exhibited a stronger association with the development of renal disease compared to aminoglycosides. ConclusionCurrent aminoglycoside use did not contribute to a higher incidence of lasting renal disease compared to other antibiotics but was linked to increased morbidity and mortality. Caution is crucial when administering aminoglycosides to elderly patients to prevent adverse outcomes.

Vestibular Hypofunction Secondary to Topical Use of Aminoglycosides in Ears with Perforated Tympanic Membrane

Introduction: The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media. Material and Methods: An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past 10 years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals. Results: During the study period, 6 patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due to infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and 4 were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, 4 patients experienced sequelae, with 2 patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life. Conclusions: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy.

WHO AWaRe Method for Analysis of Clinical Practice of Antimicrobial Therapy in Children's Multidisciplinary Hospitals in Russia

The new AWaRe classification proposed by WHO for assessing the clinical practice of using antibiotics in adults in 2017 was adapted for children's hospitals in 2019, due to the update of the categorization of antimicrobials, and showed effec- tiveness for assessing the rationality of antimicrobials use in children's hospitals in WHO-participating countries in the observation protocol GARPEC. In this retrospective pharmacoepidemiological study, we assessed the rationality of antibiotic consumption in multidisciplinary hospitals in the subjects of the Russian Federation with a pediatric profile. An observational multicenter study of antibiotic consumption was carried out in the constituent entities of the Russian Federation (N=9). Consumption assessment was carried out using the AWaRe method, based on DDD analysis and the WHO list of essential antibiotics for children by groups: «Access» (green), «Watch» (yellow) and «Reserve»(red). The quantitative indicator «the number of days of therapy in the ATC group J01 Antibacterial drugs for systemic use» in the established standardized dose per 100 patient days in the pediatric profile in level III hospitals in 9 regions of Russia for 2021 was 214.93. On average, each of the hospitalized pediatric children received at least two antibiotics during the period of hospital treatment in 2021 in Russia. On average, in Russia, based on the results from 9 constituent entities of the Russian Federation, drugs in the «Admission» category were 44.24%, «Control» — 49.23%, «Reserve» — 0.88%. When categorizing according to WHO2019, negative characteristics were identified — either excessive use of cefazolin and amikacin in the «Access» category, or the predominance of drugs with antipseudomonas activity, ceftazidime and cefepime, in the «Watch» groups. A positive and more balanced version of the structure of antibiotic consumption in multidisciplinary children's hospitals was identified in Moscow («Access» — 37.3%, «Watch» — 59.29%, «Reserve» — 3.41%), in the Republic of Mari El («Access» — 30.28%, «Watch» — 69.42%, «Reserve» — 0.30%) and in the Republic of Khakassia («Access» — 30.95%, «Watch» — 67.39%, «Reserve» — 1.66%). Thus, «Access» (green), the main indicator of the assessment category of antibiotic consumption in children, did not reach 60% in 2021 in any of the multidisciplinary children's hospitals in Russia presented in this study, which was proposed as a target indicator for achieving rational consumption according to WHO. The results of this study showed the problems of irrational use of antibiotics: insufficient use of oral dosage forms in children, excessive use of aminoglycosides, unjustified switching to combination antimicrobial therapy with antibiotics of the «Reserve» group in multidisciplinary children's hospitals in Russia.

A comparison of aminoglycoside antibiotic serum concentrations collected by peripheral veins and peripherally inserted central catheters in adults with cystic fibrosis.

People with cystic fibrosis (PwCF) are frequently hospitalized for treatment of pulmonary exacerbation. The Cystic Fibrosis Foundation Pulmonary Guidelines support the use of intravenous aminoglycosides with therapeutic drug monitoring for the treatment of pulmonary exacerbation due to Pseudomonas aeruginosa. Serum intravenous tobramycin concentrations are commonly collected by peripheral venipuncture (PV). Discomfort associated with collection of samples by PV prompts collection via PICC, but the accuracy of intravenous tobramycin serum levels collected by PICC has not been documented in adult PwCF. The primary study objective was to evaluate the difference between intravenous tobramycin serum levels collected by PV and PICC in adult PwCF. The authors conducted a prospective case-control study of adult PwCF admitted to University of Utah Health for a pulmonary exacerbation receiving tobramycin by a single lumen PICC. The authors compared tobramycin peak and random serum levels collected by PV and PICC using a detailed flush and waste protocol. The authors analyzed a total of 19 patients with peripheral and PICC samples. The mean tobramycin peak collected by PV (27.2 mcg/mL) was similar to the mean peak collected by PICC (26.9 mcg/mL) (paired samples Wilcoxon signed-rank test, p = .94). The correlation coefficient was 0.88 (95% CI = 0.85-0.91, p < .001). Tobramycin serum samples collected by PICC appear to be similar in value to PV collections. Collecting aminoglycoside levels by PICC rather than PV may reduce patient discomfort and improve quality of life. Additional multicenter studies are needed to confirm these results.

Prospective evaluation of single-dose aminoglycosides for treatment of complicated cystitis in the emergency department.

Antimicrobial resistance among Enterobacterales continues to be a growing problem, particularly in those with urinary infections. Previous studies have demonstrated safety and efficacy with the use of single-dose aminoglycosides in uncomplicated cystitis. However, data in complicated infections are limited. Single-dose aminoglycosides may provide a convenient alternative for those with or at risk for resistant pathogens causing complicated urinary infections, especially when oral options are unavailable due to resistance, allergy, intolerance, or interactions with other medications. This study evaluated the safety and effectiveness of single-dose aminoglycosides in treatment of complicated cystitis in the emergency department (ED). This was a multicenter, prospective study performed between July 2022 and March 2023 of patients who met criteria for complicated cystitis and were otherwise stable for discharge at an academic ED. Primary outcomes were clinical or microbiologic failure within 14 days of treatment. Safety was assessed by review of adverse events. Descriptive statistics were used. Thirteen patients were included. Complicating factors were male sex (n = 4), kidney stone (n = 2), urinary catheter (n = 6), recent urologic procedure (n = 1), urinary hardware (n = 1), antibiotic allergy precluding use of alternate oral options (n = 4), immunocompromised status (n = 2), and <1-year history of multidrug-resistant organisms on urine culture (n = 8). Eleven patients (85%) had positive urine cultures in the preceding 12 months with no oral antimicrobial option. Eight patients (62%) received amikacin (median dose 15 mg/kg), four patients (31%) received gentamicin (median dose 5 mg/kg), and one patient (8%) received tobramycin (5 mg/kg) for treatment. Ten patients (77%) reported resolved urinary symptoms after treatment and 11 patients (85%) reported no new urinary symptoms since discharge. No patient required hospital admission for treatment failure, and no adverse events were noted. Single-dose aminoglycosides appear to be a reasonably effective and safe treatment for complicated cystitis, which avoided hospital admission in this cohort.

Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations

Rett syndrome (RTT) is a neurodevelopmental disorder resulting from genetic mutations in the methyl CpG binding protein 2 (MeCP2) gene. Specifically, around 35% of RTT patients harbor premature termination codons (PTCs) within the MeCP2 gene due to nonsense mutations. A promising therapeutic avenue for these individuals involves the use of aminoglycosides, which stimulate translational readthrough (TR) by causing stop codons to be interpreted as sense codons. However, the effectiveness of this treatment depends on several factors, including the type of stop codon and the surrounding nucleotides, collectively referred to as the stop codon context (SCC). Here, we develop a high-content reporter system to precisely measure TR efficiency at different SCCs, assess the recovery of the full-length MeCP2 protein, and evaluate its subcellular localization. We have conducted a comprehensive investigation into the intricate relationship between SCC characteristics and TR induction, examining a total of 14 pathogenic MeCP2 nonsense mutations with the aim to advance the prospects of personalized therapy for individuals with RTT. Our results demonstrate that TR induction can successfully restore full-length MeCP2 protein, albeit to varying degrees, contingent upon the SCC and the specific position of the PTC within the MeCP2 mRNA. TR induction can lead to the re-establishment of nuclear localization of MeCP2, indicating the potential restoration of protein functionality. In summary, our findings underscore the significance of SCC-specific approaches in the development of tailored therapies for RTT. By unraveling the relationship between SCC and TR therapy, we pave the way for personalized, individualized treatment strategies that hold promise for improving the lives of individuals affected by this debilitating neurodevelopmental disorder. Key messagesThe efficiency of readthrough induction at MeCP2 premature termination codons strongly depends on the stop codon context.The position of the premature termination codon on the transcript influences the readthrough inducibility.A new high-content dual reporter assay facilitates the measurement and prediction of readthrough efficiency of specific nucleotide stop contexts.Readthrough induction results in the recovery of full-length MeCP2 and its re-localization to the nucleus.MeCP2 requires only one of its annotated nuclear localization signals.

Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021.

Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.

Risk Factors for Acute Kidney Injury in Patients Receiving Intravenous Colistin

Background: Colistin use is primarily associated with nephrotoxicity, which has been shown to be reversible with a low incidence of long-term kidney impairment. This study aimed to investigate the risk factors for acute kidney injury (AKI) in patients receiving intravenous colistin. Methods: A retrospective cohort study was conducted at Nakornping Hospital in northern Thailand from 2015 to 2020. Adult patients who received intravenous colistin were included, while those with chronic kidney disease or prior renal replacement therapy were excluded. The study assessed potential AKI risk factors, including demographics, comorbidities, and concurrent use of medications. Cases of AKI are identified among the cohort, while the control group includes individuals not experiencing AKI during the follow-up but similar to the cases in terms of the exposure. Univariate and multivariable logistic regression analyses were performed to identify risk factors associated with AKI. Results: Among the 206 patients included in the study, a majority were admitted to the intensive care unit, required mechanical ventilation, and experienced septic shock. Univariate analysis revealed diabetes (odd ratio (OR)=2.82, 95% CI: 1.21–6.59, p=0.016), malignancy (OR=2.06, 95% CI:1.12–3.77, p=0.020), and baseline Scr (OR=0.71, 95% CI: 0.51–0.99, p=0.048) as significant risk factors for AKI. Multivariate analysis confirmed the association of diabetes (adjusted odd ratio(aOR)= 3.09, 95% CI: 1.20–7.96, p=0.019), malignancy (aOR= 2.31, 95% CI: 1.18–4.52, p=0.015), septic shock (aOR = 2.80, 95% CI: 1.02–7.69, p=0.045), and vasopressor use (aOR = 2.85, 95% CI: 1.12–7.23, p=0.028) with an increased risk of AKI. Conversely, baseline Scr (aOR = 0.54, 95% CI: 0.36–0.82, p=0.004) were associated with a decreased risk of AKI. Other factors, including concomitant use of aminoglycosides, vancomycin, rifampin, combination therapy, nephrotoxins, hypertension, and intensive care unit admission, did not show significant associations. Conclusion: This study identified diabetes, malignancy, septic shock, and vasopressor use as significant risk factors for AKI in patients receiving colistin. Baseline Scr levels were found to be inversely associated with the risk of AKI. These findings contribute to a better understanding of colistin-related nephrotoxicity and can guide clinical management to mitigate the risk of AKI in this patient population.

P03 Amikacin drug levels and efficacy—a 3 month remissive study

Abstract Background The therapeutic drug monitoring (TDM) of toxic drugs is a routine practice in our 200-bed hospital. Amikacin is not often used except in MDR bacteria. TDM is based on trough and peak levels of aminoglycosides, although AUC TDM may be the way forward, as discussed in the conclusions. According to the literature, measurement of serum amikacin levels is indicated in cases when prolonged aminoglycoside therapy is expected or in patients with compromised renal function and is not recommended for aminoglycoside use for less than 5–7 days or for treatment of mild infections in patients with no risk factors for drug toxicity. Objectives This study delivers some controversy on not to recommend monitoring for aminoglycoside use for less than 5–7 days, or for treatment of mild infections in patients with no risk factors for drug toxicity. Methods A retrospective study was conducted in our hospital between May and June 2023. Five patients aged 62–82 years on amikacin therapy for 5 to 10 days were included, all with Klebsiella pneumoniae OXA-48 UTI. At least two peak and trough samples were collected, and data were submitted to the Precise PK© software for precision dosing. The software is designed to predict population-based levels and patient-based levels. Interpretation of these values by pharmacists delivers optimized/viable amikacin intervals and dose individualized recommendations. Results Results are shown in Table 1. Conclusions Serum amikacin monitoring should guide therapy to ensure adequate levels, especially in Gram-negative resistant bacterial infections. According to these results, with Gram-negative resistant bacteria, it is worth monitoring even the short treatments—as seen in Patient 3. AUC TDM instead of peak TDM might be the way forward— this obviates distribution phase underdosing and delivers more accurate correlation to efficacy after changing intervals.

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance.

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

Clinical Observations in Patients With Cystic Fibrosis-Related Diabetes and Self-Reported Ototoxicity Symptoms.

Persons with cystic fibrosis (PwCF) are at high risk for ototoxicity due to the routine use of intravenous aminoglycoside (IV-AG) antibiotics in respiratory infection management. Additionally, factors that contribute to ototoxicity-related symptom development and severity in PwCF are unknown. Given the increased risk of ototoxicity in people with diabetes, we explored the association between cystic fibrosis-related diabetes (CFRD) and self-reported ototoxicity symptoms (tinnitus and vestibular problems) in PwCF treated with aminoglycosides. PwCF (N = 39; 25 females, 14 males; Mage = 30.1 years, SD = 10.3) were recruited from the Cystic Fibrosis Care Center at Oregon Health & Science University. Patients completed the validated questionnaires to ascertain their experiences with ototoxicity-related symptoms of tinnitus and balance function. The diagnosis of CFRD, including oral glucose tolerance testing (OGTT), insulin treatment, hemoglobin A1c, and cumulative IV-AG treatment history, was obtained through a medical chart review. Participants were classified into three groups based on their medical diagnoses via OGTT: normal glucose tolerance (NGT; control; n = 16), abnormal glucose tolerance (AGT; n = 9), and CFRD (n = 14). Participants in each group were further classified based on survey outcomes for ototoxicity-related symptoms. There was a trend toward a higher proportion of patients with CFRD reporting tinnitus compared to the AGT and NGT groups, but did not meet statistical significance (X2 = 2.24, p = .13). Approximately, 43% of patients with CFRD reported experiencing clinically significant tinnitus lasting > 3 min compared to 11% in the AGT group and 13% in the NGT group (X2 = 3.751, p = .05). Cumulative IV-AG exposure tended to be higher in CFRD compared to other groups. High balance function was generally reported in all groups. Patients with CFRD have greater ototoxicity-related symptoms. Further investigation of the relationship between CF-related comorbidities and the risk of developing ototoxicity-related symptoms is warranted to improve the detection and management of ototoxicity in PwCF.

2781. The Use of Aminoglycosides for Treatment of Urinary Tract Infections in Pediatric Patients, a Carbapenem-Sparing Approach

Abstract Background Urinary tract infections (UTIs) caused by antimicrobial-resistant pathogens have been increasingly reported. Aminoglycosides are known to be effective therapy for UTIs, however their use is not common due to a fear of nephrotoxicity. Overuse of broad-spectrum antimicrobial agents, particularly carbapenems can lead to colonization with carbapenem-resistant pathogens resulting in more difficult-to-treat infections. We aim to evaluate the use of aminoglycosides for UTI therapy in pediatric patients to assess the clinical outcome. Methods A retrospective chart review was performed to evaluate all orders of aminoglycosides for the indication of UTI from 2020-2022 at Children’s Hospital Los Angeles. Demographic data, bacterial pathogen, kidney function before and during treatment, and clinical outcomes were collected and analyzed. We also evaluated the resistance patterns of bacterial pathogens, and whether they met our institutional criteria of a multi-drug resistant organism (MDRO). Patients were excluded if they received ≤ 48hrs of treatment with an aminoglycoside or if they did not have a gram-negative pathogen identified on urine culture. Results A total of 61 patient encounters included an aminoglycoside order for treatment of UTI during the review period. 45 out of 61 encounters had a positive urinary culture that met our institutional criteria for an MDRO. Among patients receiving aminoglycosides, we observed 4 cases of elevated sCr that met our definition of AKI. The 2 cases with the greatest creatine increase (3-4 x baseline), were also currently receiving empiric vancomycin treatment. No patients had a documented treatment failure requiring change or escalation in therapy, or lack of resolution of fever. Four cases had a recurrence within 30 days after discharge. Three out of the four patients with recurrence had pre-existing anatomical abnormalities of the urinary tract that put them at increased risk for recurrent infection. Conclusion Overall, extended interval aminoglycoside therapy was effective and well-tolerated for the treatment of urinary tract infections in our pediatric patient population. For cases of multi-drug resistant urinary pathogens, aminoglycosides represent a reasonable alternative to broader spectrum options such as carbapenems. Disclosures All Authors: No reported disclosures

Cortisol Sensitizes Cochlear Hair Cells to Gentamicin Ototoxicity Via Endogenous Apoptotic Pathway.

The widespread use of aminoglycosides is a prevalent cause of sensorineural hearing loss. Patients receiving aminoglycosides usually have elevated levels of circulating stress hormones due to disease or physiological stress; however, whether the stress hormone cortisol impacts aminoglycoside-mediated injury of cochlear hair cells has not been fully investigated. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells with or without cortisol pretreatment were exposed to gentamicin, we investigated the effect of cortisol pretreatment on gentamicin ototoxicity by assessing cell viability. Molecular pathogenesis was explored by detecting apoptosis and oxidative stress. Meanwhile, by inhibiting glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), the potential roles of receptor types in cortisol-mediated sensitization were evaluated. Cortisol concentrations below 75 μmol/l did not affect cell viability. However, pretreatment with 50 μmol/l cortisol for 24 hours sensitized hair cells to gentamicin-induced apoptosis. Further mechanistic studies revealed that cortisol significantly increased hair cell apoptosis and oxidative stress, and altered apoptosis-related protein expressions induced by gentamicin. In addition, blockade of either GR or MR attenuated cortisol-induced hair cell sensitization to gentamicin toxicity. Cortisol pretreatment increased mammalian hair cell susceptibility to gentamicin toxicity. Sensitization was related to the activation of the intrinsic apoptotic pathway and excessive generation of reactive oxygen species. Cortisol may exacerbate aminoglycoside ototoxicity.

Tularemia – a re-emerging disease with growing concern

Tularemia caused by Gram-negative, coccobacillus bacterium, Francisella tularensis, is a highly infectious zoonotic disease. Human cases have been reported mainly from the United States, Nordic countries like Sweden and Finland, and some European and Asian countries. Naturally, the disease occurs in several vertebrates, particularly lagomorphs. Type A (subspecies tularensis) is more virulent and causes disease mainly in North America; type B (subspecies holarctica) is widespread, while subspecies mediasiatica is present in central Asia. F. tularensis is a possible bioweapon due to its lethality, low infectious dosage, and aerosol transmission. Small mammals like rabbits, hares, and muskrats are primary sources of human infections, but true reservoir of F. tularensis is unknown. Vector-borne tularemia primarily involves ticks and mosquitoes. The bacterial subspecies involved and mode of transmission determine the clinical picture. Early signs are flu-like illnesses that may evolve into different clinical forms of tularemia that may or may not include lymphadenopathy. Ulcero-glandular and glandular forms are acquired by arthropod bite or handling of infected animals, oculo-glandular form as a result of conjunctival infection, and oro-pharyngeal form by intake of contaminated food or water. Pulmonary form appears after inhalation of bacteria. Typhoidal form may occur after infection via different routes. Human-to-human transmission has not been known. Diagnosis can be achieved by serology, bacterial culture, and molecular methods. Treatment for tularemia typically entails use of quinolones, tetracyclines, or aminoglycosides. Preventive measures are necessary to avoid infection although difficult to implement. Research is underway for the development of effective live attenuated and subunit vaccines.

Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients.

Aminoglycosides are broad-spectrum antibiotics largely used in children, but they have potential toxic side effects, including ototoxicity. Ototoxicity from aminoglycosides is permanent and is a consequence of its action on the inner ear cells via multiple mechanisms. Both uncontrollable risk factors and controllable risk factors are involved in the pathogenesis of aminoglycoside-related ototoxicity and, because of the irreversibility of ototoxicity, an important undertaking for preventing ototoxicity includes antibiotic stewardship to limit the use of aminoglycosides. Aminoglycosides are fundamental in the treatment of numerous infectious conditions at neonatal and pediatric age. In childhood, normal auditory function ensures adequate neurocognitive and social development. Hearing damage from aminoglycosides can therefore strongly affect the normal growth of the child. This review describes the molecular mechanisms of aminoglycoside-related ototoxicity and analyzes the risk factors and the potential otoprotective strategies in pediatric patients.

Factors associated with colonization by carbapenem-resistant enterobacteria in oncological patients: a case-control study

Introduction: Colonization and infections caused by Carbapenemase Producing Enterobacteria (CPE) are a global problem, being associated with an increase in hospitalization time, costs for health services, and morbidity and mortality rates. Oncologic patients represent a group of special interest and there are few studies involving CPE colonization among these patients. Aim: to investigate factors associated with colonization in cancer patients. Outlining: Case-control study developed in a tertiary reference hospital in cancer treatment in Porto Alegre, Brazil, from January to December 2017. The population consisted of patients diagnosed with cancer in clinical or surgical hospitalization. Results: The univariate analysis showed that variables associated with colonization by CPE were age, male sex, tumors with bone type of surgical hospitalization, number of intra-hospital transfers since hospitalization, hospitalization time &gt;30 days, ICU hospitalization in the last 30 days, ICU time more than 15 days, surgical procedure in the last 30 days, use of antibiotics in the last 30 days, presence of tumor wound, and KPC infection. After multivariate analysis, male sex, external hospital as origin, hospital stay longer than 30 days, antibiotic use in the last 30 days, and presence of tumor wound, remained associated with EPC colonization. Use of aminoglycosides, and linezolide were associated with CPE colonization. Implications: We identified variables associated with CPE colonization in oncologic patients. Our results may indicate actions to prevent CPE colonization and consequent development of infections.